VHL / HIF oxygen sensing
The VHL/HIF pathway is how cells sense oxygen (the 2019 Nobel Prize). VHL destroys HIF when oxygen is present. Kidney cancers lose VHL, so HIF-2α is permanently on and drives blood vessel growth and proliferation.
Overview
In normoxia, prolyl hydroxylases (PHD) hydroxylate HIF-α, allowing the VHL E3 ligase to ubiquitinate it for proteasomal degradation. In hypoxia (or with VHL loss in ~90% of clear-cell RCC), HIF-α accumulates, dimerises with HIF-1β (ARNT), and transcribes VEGF, PDGF, GLUT1, CAIX, cyclin D1, and EPO. HIF-2α is the oncogenic paralogue in RCC; belzutifan blocks its dimerisation. CAIX is a PET and radioligand target (89Zr-girentuximab).
Analogy
VHL is the shredder that destroys the 'we are suffocating' memo whenever there is oxygen around. Kidney cancer breaks the shredder, so the memo piles up and the cell keeps ordering new blood vessels and sugar.
Diagram
top- Belzutifan (HIF-2α) in VHL disease and RCC, adjuvant with pembrolizumab (2026)
- VEGF-directed therapy downstream
- CAIX-targeted imaging (89Zr-girentuximab) and radioligands in development
Similar pages
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